University of Massachusetts Amherst researchers have revealed how a microRNA molecule known as Lethal-7 (let-7) serves as a molecular control hub to direct the function of cytotoxic T lymphocytes by putting the brakes on their cell-killing activities.
Molecular biologists led by Leonid Pobezinsky found that when let-7 levels are low or absent, the body's T cells can potentially turn into "super killers.
Normally RNA codes proteins, but microRNA do not. Instead, these tiny RNA snips have regulatory activity on the whole genome. This series of experiments, detailed in a recent eLife paper, was sparked by the observation that T cells produce a lot of let-7 molecules, and when T cells are in their inactive state with no pathogen present, T cells are full of these let-7 cells. But the moment they see an antigen, suddenly the let-7s are gone, which prompted the team to ask: “What do they regulate and why do they need to disappear?"
The researchers hypothesized that in the presence of microRNA let-7 molecules, T cells are quiet, which for the organism is a safe condition with the immune system inactive. But when a threat is sensed, let-7 molecules disappear, which allows T cells to become functionally cytotoxic and able to clear pathogens, including tumor cells.
“Our hypothesis turns out to be correct,” Pobezinsky says. “In fact the microRNAs work as a brake on the cytotoxic T cells when there is no antigen present, so when we are healthy, they rest. As soon as they are gone, T cells initiate differentiation into cytotoxic T lymphocytes."
In experiments with three groups of mice: wild type controls, mice genetically modified to have no let-7, and another group engineered to have a super abundance of let-7, the researchers found that the complete absence of let-7 yielded the strongest differentiation of T cells to killer status. "If you keep let-7, T cells cannot become cytotoxic even in the presence of tumor or virus," Pobezinsky says. "If you have none or almost none, function is enhanced."
"We also figured out the molecular pathway using transcription factors that regulate the T cell differentiation and confirmed that let-7 microRNA is the most critical control," he adds. The researchers now hope that this might lead to the ability to modulate immune responses that are regulated by CD8 cells, and they are testing it on mouse tumor models to try to enhance immune response against tumors using this technique.
"We'd like to develop a way to suppress or enhance immune response," Pobezinsky says. "We might be able to combine this with adaptive immunotherapy to enhance immune function, so we would use a person's own T cells, treat them in vitro, then to put back super killer T cells to boost their immune response."